Lercanidipine (methyl 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate) is a highly lipophilic dihydropyridine calcium antagonist with a long duration of action and high vascular selectivity. Lercanidipine is a high affinity competitive antagonist of the dihyropyridine subunit of the L-type calcium channel.
Lercanidipine is useful as an anti-hypertensive. Lercanidipine treatment lowers blood pressure by blocking calcium channels of arterial smooth muscle, thus decreasing peripheral vascular resistance. Lercanidipine produces no negative cardiac inotropism and only occasional, mild reflex tachycardia, generally of short duration. Lercanidipine has been approved for the treatment of hypertension in Europe and has been marketed since 1996 in several European countries under the trademark Zanidip™.
The hydrochloride salt of lercanidipine is commercially available from Recordati S.p.A. (Milan, Italy). Methods of making both lercanidipine free base and the lercanidipine hydrochloride salt along with methods of resolving lercanidipine into individual enantiomers are described in U.S. Pat. Nos. 4,705,797; 5,767,136; 4,968,832; 5,912,351; and 5,696,139, all of which are incorporated herein by reference.
A major disadvantage of the process of preparing lercanidipine, as it is described in U.S. Pat. No. 4,705,797, is that the disclosed cyclization reaction generates several by-products, which results in a lower yield for the desired product. U.S. Pat. No. 5,912,351 describes a simpler process for the preparation of lercanidipine hydrochloride. The process yields lercanidipine hydrochloride in an anhydrous non-hygroscopic crystalline form, avoiding the formation of unwanted by-products and need for subsequent purification on chromatography columns.
However, the isolation of lercanidipine hydrochloride in crystalline form is again quite complex. Additionally, the lercanidipine hydrochloride may exist as any one of at least four distinct polymorphs, each of which has distinct physical properties (see, U.S. Pat. No. 6,852,737 and U.S. Patent Publication No. 2003/0069285). Therefore, there is a need in the art for simpler processes of producing lercanidipine salts, especially crystalline lercanidipine salts. There is also a need for lercanidipine salts that have solubility and/or other physical properties that are distinct from, and preferably more desirable than, the previously isolated forms of lercanidipine hydrochloride, including, but not limited to, reduced inter-patient variability, reduced food effect, and little or no polymorphism.